Efficacy and effectiveness of 20 child health interventions in China: Systematic review of Chinese literature.

Aim The research production of the Chinese academics for the past few decades, which is being published in more than nine thousands of Chinese academic periodicals, has recently been digitalized and made available in the public domain. The aim of this study was to systematically identify and assess the evidence from Chinese literature sources on the efficacy and effectiveness of child health interventions in China. Methods The Chinese National Knowledge Infrastructure databases were searched for the studies with primary data on efficacy or effectiveness of child health interventions in China between 1980 and 2011. The searches of PubMed and the ‘Lives Saved Tool (LiST)’ evidence base were also performed to identify the counterpart evidence in the English language. Results Of 32 interventions initially identified in the Chinese literature, 20 interventions sustained the primary information addressing efficacy or effectiveness. Among preventive interventions (14 interventions), most studies were dedicated to complementary feeding (7 studies), kangaroo mother care (7 studies) and syphilis detection and treatment (4 studies). Among treatment interventions (6 interventions), the most frequently studied were zinc for treatment of diarrhoea (11 studies) and newborn resuscitation (9 studies). The evidence on efficacy or effectiveness of the 32 interventions conducted in Chinese children in the Chinese literature was either of comparable quality, or more informative than the available reports on China in the English literature, which rarely contained studies on child health intervention effectiveness exclusively in Chinese population. The included studies reported positive results unanimously, implying a likely publication bias. Discussion The evidence on the efficacy and effectiveness of child health interventions in China is typically modest in quantity and quality, and implies a notable urban-rural discrepancy in applied health systems research to improve child health interventions and programmes. However, it is clear that considerable research interests and initiatives from both inside and outside the country have been concentrating on implementation, long-term operation, evaluation and further development of child health interventions, especially preventive interventions in China.

In 2000, the UN defined a set of goals on which a global political consensus was reached -the 'Millennium Development Goals' (1,2). The fourth goal was defined as an ambition to decrease the levels of global child mortality between 1990 and 2015 by two thirds (3). The leading strategies for achieving child mortality reduction were to implement cost-effective interventions in the largest part of the population in low and middle income countries (4)(5)(6)(7). These interventions were developed to prevent and treat the leading causes of child mortality, eg, preterm birth complications, birth asphyxia, neonatal infections, pneumonia, congenital abnormalities, diarrhoea, tetanus and HIV/AIDS (5,6). Clearly, there are many possible interventions available, and prioritization of those interventions for implementation among children has become one of the most important health policy goals for the governments, especially in low and middle income countries (8). They are calling for better evidence on the efficacy, effectiveness and cost-effectiveness of each intervention, and also better information on the patterns of child mortality burden in their countries (8). Therefore, understanding the causes of child mortality and the effectiveness of the preventive and treatment interventions has become one of the main interests of the global health community. The 'Child Survival Series' published by The Lancet is the earliest and one of the best examples (5,(9)(10)(11)(12).
The controversy over the true value of many child health interventions still rekindle debates now and then. First, once a few published randomized controlled trials show effectiveness of an intervention, it becomes unethical to scale up the evaluation only to deprive the control arm of apparent benefits. Second, the diversity of study settings and contexts produces enormous confounding and distorts generalization. Third, due to resource constraints, not every study can achieve sufficiently large simple size. Many of them eventually become underpowered, which leads to diverse and often conflicting results. Furthermore, mortality is rarely -if ever -an acceptable outcome of an intervention trial, and the introduction of proxy indicators creates uncertainty over the true effects on mortality and causes ambiguous conclusions. The most recent effort to integrate estimated effectiveness of interventions on child mortality has been published in 2 supplements of the International Journal of Epidemiology and BMC Public Health, providing the theoretical and methodological background information for the 'Lives Saved Tool (LiST)' (13). LiST is an evidence-based software module that allows prediction of the impact of scaling up different child health interventions at the national, regional and global level. Although this project is designed and performed to produce reasonably conservative estimates, the primary information gap is still an open issue and that new evidence from any proper sources would further refine the estimates.
One of the potential sources of this kind is academic literature in the Chinese language. The research production of Chinese academics for the past few decades, which is being published in more than nine thousands of Chinese academic periodicals, has recently been digitalized and made available in the public domain. It has been proven that strategically retrieving and analysing qualified publications in the Chinese literature contributes significant evidence and updates to the understanding and knowledge on various topics in the field of child health epidemiology (14). The aim of this study was to systematically identify and assess the evidence from Chinese literature sources on the efficacy and effectiveness of child health interventions in China.

METHODS
The China National Knowledge Infrastructure (CNKI) databases were searched for the period January 1980 to March 2011. CNKI is the most complete source of academ-  ic information in China and represents the Chinese equivalent of PubMed or the Web of Knowledge (15). A systematic search of CNKI was performed to identify clinical and community-based studies with primary data reporting either efficacy or effectiveness of child health interventions  relevant to neonates, infants, pre-school children or parents in China. Studies were included if: the total cohort was more than 50 subjects; the study design was prospective; the sample population was exclusively Chinese who lived in China at long-term residency base (16,17).
The search terms used were various combinations from a set of terms for 'efficacy' and 'effectiveness' in their Chinese equivalences, i.e. '效果', '评价', '影响', etc. and a set of terms for each intervention in their Chinese equivalences as well, eg, '叶酸', '维生素B', '补充', etc. for 'folic acid (vitamin B) supplementation'. The first step was to search prevention and treatment interventions targeting causes of child death in general (early development-related excluded). As this search strategy aimed to be as inclusive as possible, it resulted in 6476 publications which mentioned 32 interventions ( Table 1). The first level screening based on titles left 649 studies for further identification as the majority were not relevant at all to the topic of 'efficacy' or 'effec- Figure 2 The time trend of 59 retained studies during 1980-2011. I -interventions, C -controls, LBW -low birth weight, MDI -mental developmental index, PDI -psychomotor developmental index, Hb -hemoglobin concentration, IDA -iron deficiency anaemia, DQ -developmental quotient, BW -birth weight, HC -head circumference tiveness'. The abstract screening then left 136 relevant records for full text retrieving. Eventually, 59 studies (up to 1% of the initial screen) for 20 interventions were retained ( Table 2). The most common reasons for exclusion were: 1. the total sample cohort was less than 50 subjects, considering that the small sample size might lead to large errors; 2. study design was retrospective, which might cause massive recall bias; 3. the study method was not sufficiently described to understand or interpret the results.

RESULTS
The distribution of the 59 included studies clustered mainly in the eastern and central regions of China (Figure 1). All the included studies that evaluated a total of 20 interventions were focused on addressing efficacy or effectiveness as the primary outcome. Among preventive interventions (14 interventions), most studies were dedicated to complementary feeding (7 studies), kangaroo mother care (7 studies) and syphilis detection and treatment (4 studies) ( Table 3). Among treatment interventions (6 interventions), the most frequently studied were zinc for treatment of diarrhoea (11 studies) and newborn resuscitation (9 studies) ( Table 4). Within each intervention, the results from individual studies generally supported each other, providing evidence on the positive effects for all interventions. However, several peculiarities need to be noted: for complementary feeding, each study adopted different food formulas and this may be due to the widespread geographic distribution. For Kangaroo mother care, the research interests varied dramatically, which made the targeting outcomes very diverse -including body temperature management, pain management, weigh gain, physiological and behavioural factors, etc. For syphilis detection and treatment, it was no-table that one community-based study conducted in Guangdong province and recruiting 186 517 subjects reported an impressive 61.90% reduction rate during a period of two years. For zinc for treatment of diarrhoea, although OER and anti-diarrhoea duration were common indicators, the ingredients and portions of zinc formula adopted in each study were not consistent. Finally, for newborn resuscitation the universal outcome indicators employed in each study were Apgar-5 and Apgar-10, while Apgar-1 and Apgar-7 occasionally reported with other specific outcomes such as mortality, morbidity of asphyxia, pneumonia and infections.
The evidence on efficacy or effectiveness of the 32 interventions conducted in Chinese children in the Chinese literature was either of comparable quality, or more informative than the available reports on China in the English literature ( Table 5). Although the selected English literature sources showed a substantial and strikingly increasing number of publications on child health interventions during the same period, studies on intervention effectiveness exclusively in Chinese children were very rarely published, and the few rare studies were unlikely to scale-up a systematic analysis or meta-analysis for any of the 32 selected interventions in this paper.

DISCUSSION
This paper represents the very first attempt to systematically investigate the accessibility, quantity and quality of the research production of Chinese academics over the period of the past 30 years on efficacy and effectiveness of child health interventions in China. It is possible that a parallel review and/or the extended systematic review of other digital Chinese-language databases such as Chongqing VIP and Wanfang would have identified slightly more studies. However, the initial searching within the two additional databases did not seem to add any further evidence (my search on February 15, 2011), and this might due to the extremely massive overlap in indexed journals of the three domains (15,18,19). It is very unlikely that substantial omissions could have drawn dramatically different conclusions on quantity assessment from those that this paper offers.
Conducting studies which evaluate interventions generally not only requires substantial financial support and highlevel technical expertise, but it is also subject to various vital factors, such as ethical approval, unique local conditions/customs and liaisons with multiple-organizations, to name a few. Usually, a single team of researchers has to invest tremendous efforts to ensure smooth workflow for years to achieve the ultimate outcome, either positive or negative, even possessing sufficient essential resources.
Jian Shayne F. Zhang  This may explain why, in the global context, the research production on intervention evaluation is relatively scarce and the relevant studies with large sample sizes and robust study designs are extremely valuable.
According to GRADE criteria, the retained studies in the Chinese literature are generally of modest quality (17). Relatively small sample sizes and wide confidence intervals make it unjustified that all retained studies should be expected to show positive effects of the investigated interventions, implying a likely publication bias. This has not ridden the Chinese literature only, as there is a traditional academic and industrial resistance to reporting and pursuing publication of negative effects, especially where the previous evaluation showed benefits. China may consider incorpo-rating the existing national ethics approval system with a mandatory national trail registration system in order to keep all the trails conducted in China well tracked and ensure that the final outcomes are reported and made public.
Despite insufficient information to fully assess the current situation of child health interventions in depth in China, the urban-rural discrepancy in study distribution and funding resources is particularly notable. While the studies in Eastern and Central China were conducted by regional leading institutes as scientific research projects, Western China, the most remote and mountainous region of the country, seems to still be reliant on overseas aid to implement child health interventions. The longstanding urban-rural socio-economical imbalance results in limited academic and industrial ac- I -intervention, C -control, RR -risk ratio, AR -attribute ratio, ARP -attribute ratio percentage, RDS -respiratory distress syndrome, Hb -hemoglobin concentration tivities focusing on the most underdeveloped region of China, where implementing, evaluating and further developing appropriately customized interventions may achieve highest potential impact on child mortality reduction and other aspects of child health in China as a whole.
Comprehensive and accurate data and evidence on child health interventions are indispensable for prioritizing pre-vention and treatment strategies in order to achieve optimal policy decisions. It is clear that considerable research interests and initiatives from both inside and outside the country have been concentrating on child health interventions, especially preventive interventions in China. How to best harness and facilitate those potential strengths in this still new and fast growing field could be the next opportunity and challenge that the country has to take.
Funding: This study was supported by the Bill and Melinda Gates Foundation Grant to the U.S. Fund for UNICEF.
Ethical approval: Not required.
Authorship declaration: JSFZ conceived and performed the study, analyzed and interpreted the results and wrote the article.

Competing interests:
The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.